l-701324 and 1-hydroxy-3-amino-2-pyrrolidone

Topics: Animals; Anti-Anxiety Agents; Antipsychotic Agents; Binding Sites; Cognition; Glycine; Humans; Kynurenic Acid; Neuroprotective Agents; Pyrrolidinones; Receptors, N-Methyl-D-Aspartate; Structure-Activity Relationship

Glycine encephalopathy (GE) is caused by an inherited deficiency of the glycine cleavage system (GCS) and characterized by accumulation of glycine in body fluids and various neurologic symptoms. Coma and convulsions develop in neonates in typical GE while psychomotor retardation and behavioral abnormalities in infancy and childhood are observed in mild GE. Recently, we have established a transgenic mouse line (low-GCS) with reduced GCS activity (29% of wild-type (WT) C57BL/6) and accumulation of glycine in the brain (Stroke, 2007; 38:2157). The purpose of the present study is to characterize behavioral features of the low-GCS mouse as a model of mild GE. Two other transgenic mouse lines were also analyzed: high-GCS mice with elevated GCS activity and low-GCS-2 mice with reduced GCS activity. As compared with controls, low-GCS mice manifested increased seizure susceptibility, aggressiveness and anxiety-like activity, which resembled abnormal behaviors reported in mild GE, whereas high-GCS mice were less sensitive to seizures, hypoactive and less anxious. Antagonists for the glycine-binding site of the N-methyl-D-aspartate receptor significantly ameliorated elevated locomotor activity and seizure susceptibility in the low-GCS mice. Our results suggest the usefulness of low-GCS mice as a mouse model for mild GE and a novel therapeutic strategy.

Topics: Aggression; Amino Acid Oxidoreductases; Animals; Anxiety; Binding Sites; Brain Diseases, Metabolic; Carrier Proteins; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Glycine; Mice; Mice, Inbred C57BL; Mice, Transgenic; Motor Activity; Multienzyme Complexes; Pyrrolidinones; Quinolones; Receptors, N-Methyl-D-Aspartate; Seizures; Transferases

Several partial agonist and full antagonists acting at the glycine site of the NMDA receptors were tested for potential antipsychotic-like properties in rats. As models, amphetamine- and phencyclidine (PCP)-induced locomotor activation in the open field and PCP-induced impairment of prepulse inhibition of the acoustic startle response were employed. In the open field test, partial agonists, D-cycloserine failed to show any effect, aminocyclopropane carboxylic acid (ACPC) enhanced the action of PCP (but not that of amphetamine) and R(+)HA-966 attenuated the locomotor activation produced by both amphetamine and PCP. Both full glycineB antagonists, L-701,324 and MRZ 2/576 attenuated the action of amphetamine and PCP but at the doses that also produce transient behavioural inhibition in naive animals. A competitive NMDA receptor antagonist CGP 39551 was ineffective. In the prepulse inhibition test neither L-701,324 nor MRZ 2/576 changed sensorimotor gating in naive animals nor attenuated the disrupting effects of PCP. The present data do not support antipsychotic profile of glycineB full antagonists. However, psychotomimetic potential of glycineB antagonists seems to be low.

Topics: 2-Amino-5-phosphonovalerate; Amphetamine; Animals; Antimetabolites; Antipsychotic Agents; Binding Sites; Cycloleucine; Cycloserine; Disease Models, Animal; Dopamine Agents; Drug Synergism; Excitatory Amino Acid Antagonists; Glycine; Hallucinogens; Locomotion; Male; Phencyclidine; Phthalazines; Protein Structure, Tertiary; Psychotic Disorders; Pyrrolidinones; Quinolones; Rats; Rats, Sprague-Dawley; Receptors, Glycine; Receptors, N-Methyl-D-Aspartate; Reflex, Startle

Antagonists of binding sites within the NMDA receptor complex, i.e., L-701,324 (7-chloro-4-hydroxy-3-(3-phenoxy)phenyl-2(H)quinolone), a brain penetrating glycineB receptor antagonist, and ifenprodil, a polyamine site antagonist, were tested for anticonvulsant properties in fully amygdala-kindled rats, a model of limbic epilepsy. Both drugs were not able to significantly change seizure parameters (focal afterdischarge threshold, seizure severity, and duration of seizure and afterdischarges), when administered intraperitoneally up to doses which produced severe motor impairment. However, the combination of 10 mg/kg ifenprodil and 5 mg/kg L-701,324 had a pronounced anticonvulsant effect on afterdischarge threshold and seizure severity without concomitant increase of adverse effects. These findings support the hypothesis that drugs acting only at one site of the NMDA receptor complex are ineffective, while combinations of such drugs may synergistically act to suppress limbic seizures, thus providing an adequate strategy for the treatment of this type of refractory epilepsy.

Topics: Amygdala; Animals; Anticonvulsants; Female; Kindling, Neurologic; Polyamines; Pyrrolidinones; Quinolones; Rats; Rats, Wistar; Receptors, Glycine

Dopamine metabolism, as reflected by the concentration of dihydroxyphenylacetic acid (DOPAC), in the medial prefrontal cortex was significantly increased following 30 min immobilisation stress or systemic administration of the benzodiazepine/GABA(A) receptor inverse agonist methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM). The response to stress was attenuated by pretreatment of rats with the benzodiazepine/GABA(A) receptor agonists diazepam and zolpidem. Furthermore, pretreatment with R-(+)-3-amino-1-hydroxypyrrolid-2-one (R-(+)-HA-966), a low efficacy partial agonist, and 7-chloro-4-hydroxy-3(3-phenoxy) phenylquinolin-2-(H)-one (L-701,324) a novel, high affinity, full antagonist at the glycine/NMDA receptor attenuated the response to both stress and DMCM. These results demonstrate that antagonists at the glycine/NMDA receptor complex are comparable with benzodiazepine/GABA(A) receptor agonists in their ability to prevent activation of the mesocortical dopamine system by stress and GABA(A) receptor inverse agonists. Results are discussed in relation to the interaction between glycine/NMDA receptor antagonists, the mesocorticolimbic dopamine system and stress related disorders.

Topics: Animals; Carbolines; Cerebral Cortex; Diazepam; Dopamine; Drug Evaluation, Preclinical; Excitatory Amino Acid Antagonists; GABA Agonists; Male; Pyridines; Pyrrolidinones; Quinolones; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Restraint, Physical; Stress, Physiological; Zolpidem